Free fatty acids increase PGC‐1α expression in isolated rat islets

Abstract

PGC-1a mRNA and protein are elevated in islets from multiple animal models of diabetes. Overexpression of PGC-1a impairs glucose-stimulated insulin secretion (GSIS). However, it is not well known which metabolic events lead to upregulation of PGC-1a in the b-cells under pathophysiological condition. In present study, we have investigated effects of chronic hyperlipidemia and hyperglycemia on PGC-1a mRNA expression in isolated rat islets. Isolated rat islets are chronically incubated with 0, 0.2 and 0.4 mM oleic acid/palmitic acid (free fatty acids, FFA) or 5.5 and 25 mM glucose for 72 h. FFA dose-dependently increases PGC-1a mRNA expression level in isolated islets. FFA also increases PGC-1a expression in mouse b-cell-derived bTC3 cell line. In contrast, 25 mM glucose decreases expression level of PGC-1a. Inhibition of PGC-1a by siRNA improves FFA-induced impairment of GSIS in islets. These data suggest that hyperlipidemia and hyperglycemia regulate PGC-1a expression in islets differently, and elevated PGC-1a by FFA plays an important role in chronic hyperlipidemia-induced b-cell dysfunction.

Excess Lipid Availability Increases Mitochondrial Fatty Acid Oxidative Capacity in Muscle

“…Mice with muscle-specific overexpression of lipoprotein lipase, which increases fatty acid influx into skeletal muscle, display extensive mitochondrial proliferation (32). Fatty acids have also been shown to increase PGC-1␣ expression in muscle cells (33) and ␤-cells (34), and this is associated with increased mitochondrial metabolism (33,35). The fatty acid subtype appears to be important (33), as palmitate alone reduces PGC-1␣ expression (36); however, this may be related to its activation of inflammatory pathways that are known to impact on PGC-1␣ expression (37).…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…On the other hand, PGC-1α mediates the FFA-induced pancreatic β-cell apoptosis in the development of T2DM, a process known as 'lipotoxicity'. Zhang and coworkers demonstrated that there is a direct correlation between FFAs and PGC-1α (Zhang et al 2005). After 72-h incubation, elevated FFAs (oleate/palmitate) not only dose-dependently increase PGC-1α expression level in isolated islets but also increase PGC-1α mRNA level in isolated islets and in mouse β-cell-derived bTC3 cell lines.…”

PGC-1α: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes

“…Elevations of plasma fatty acids resulting from infusion of triglyceride emulsions caused downregulation of PPARG C1A and several nuclear-encoded mitochondrial genes in skeletal muscle of healthy human subjects [82]. As fatty acids induce PGC-1α in rat pancreatic islets [76], tissuespecific regulation of PPARGC1A expression by fatty acids can be implied. PPARGC1A and PPARGC1B expression was compared in muscle biopsies from young and elderly dizygotic and monozygotic twins, before and after insulin stimulation [83].…”

“…Ucp2 could have been another effector of PGC-1α upregulation, since enhanced beta cell UCP2 level/activity diminishes glucose-induced insulin secretion in both humans and animal models [73][74][75]. The upregulation of Ppargc1a expression in diabetic animal models is not understood, but fatty acids enhance Ppargc1a expression and impair beta cell function in rat islets [76]. Also, incomplete inactivation of FOXO1 may have contributed, as FOXO1 haploinsufficiency rescued beta cell failure in mice lacking the gene for insulin receptor substrate 2 (Irs2 −/− ) [77] and a gain-of-function FOXO1 mutation targeted to liver and beta cells enhanced hepatic gluconeogenesis and impaired beta cell compensation [78].…”